Based at WSU Vancouver, lead author Deepti Singh, assistant professor in the School of the Environment, drew on hundreds of studies of climate change, air quality, agriculture, and public health to propose a “systems lens,” or scientific approach, that connects health risks with simultaneous environmental changes driven by human practices.

“The health consequences of air pollution, climate change, and transformations in agriculture are often discussed separately,” Singh said. “But these issues are all related — they have similar sources, and each one affects the others. Agricultural activities contribute to air pollution and affect regional climate patterns, while farm production and quality of crops are sensitive to air quality and climate conditions.”

Collaborating with researchers at Columbia University, the Indian School of Business, Boston University, and the University of Delaware, Singh studied the situation in South Asia, where rapid industrialization and modern farming practices have aided economic development and increased food production, but also compromised multiple dimensions of human health.

“We’re offering a framework to assess the overall health impacts from multiple parts of Earth’s natural systems, which are all changing simultaneously because of human activities,” Singh said. “The research could help identify policies and solutions that will have multiple co-benefits for the environment and human health.”

“Our work sheds new light on the ways that food systems affect, and are affected by, climate change and air pollution,” said Kyle Davis, co-author and assistant professor at the University of Delaware.

The scientists reviewed multiple examples of health impacts from changes in climate, air quality, and agricultural output, as well as co-benefits and unintended consequences of efforts to curb emissions and save water, for example. They found these examples share the need for better tools and local, high-resolution data on health, weather, emissions, air pollution, and land use to better measure human and environmental impacts.

“This study points out how useful and effective policy responses need to take multiple factors and interactions into account, and highlights the problem with simplistic explanations,” said Ashwini Chhatre, co-author and associate professor of public policy at the Indian School of Business.

Use of fossil fuels, burning of crop residue, and changes to the landscape from expansion and intensification of agriculture have contributed to extremely poor air quality in South Asia, changed the main source of rainfall, the summer monsoon, and also increased health risks for nearly a quarter of the world’s population living in the region.

“Late autumn is ‘pollution season’ in north India, and also brings vicious debates in our society about who and what are contributing to it,” Chhatre said.

Additionally, more frequent and intense heat waves and floods have killed thousands, displaced millions, lowered labor productivity, and caused disease outbreaks. Severe air pollution has contributed to increased heart and lung diseases as well as millions of premature deaths and weakened monsoonal rains. At the same time, air pollution and climate change have reduced yields of important food crops.

“While the climate benefits of reductions in greenhouse gas emissions we make today may not be felt for decades, our approach shines a light on some of the immediate health benefits, as well as unintended consequences, of policies that aim to minimize human impacts on climate and the environment,” Singh said.

In a preclinical study published in the journal Glia, Peter King, M.D., and Burt Nabors, M.D., show that their small molecule drug, SRI-42127, can potently attenuate the triggers of neuroinflammation. These experiments in glial cell cultures and mice now open the door to testing SRI-42127 in models of acute and chronic neurological injury.

Glial cells are the non-neuronal cells of the central nervous system, or CNS, that help support and protect neurons. One of the types, microglia, are brain macrophages that respond to injury or infection. “Microglia and astroglia are key cells in the central nervous system that — when activated — drive neuroinflammation by secreting toxic inflammatory mediators, including cytokines and chemokines,” King and Nabors said.

King and Nabors, both professors in the University of Alabama at Birmingham Department of Neurology, have collaborated for 25 years to study the mechanisms that trigger neuroinflammation and the role of neuroinflammation in neurological injury, degenerative disease and cancer. They say this current study builds on their prior findings that microglia and astroglia cells rely on a key RNA-binding protein called HuR that protects the messenger RNAs encoding inflammatory mediators from degradation and promotes their translation into proteins.

Neuroinflammation occurs when activated microglia and astrocytes in the brain or spinal column secrete cytokines and chemokines like IL1β, IL-6, TNF-α, iNOS, CXCL1 and CCL2. The messenger RNAs for those pro-inflammatory signaling proteins contain adenine- and uridine-rich elements, or AREs, that govern their expression.

King, Nabors and UAB colleagues have previously shown that HuR, an RNA regulator protein that binds to AREs, plays a major positive role in regulating the inflammatory cytokine production, making it a major control point in neuroinflammation.

HuR normally concentrates in the nuclei of glial cells. However, when glial cells are activated, HuR translocates out of the nucleus and into the cell cytoplasm, where it can boost production of neuroinflammatory cytokines and chemokines.

In previous work, the UAB researchers showed that HuR translocates out of the nucleus of astrocytes in the acute CNS diseases spinal column injury and stroke. They also showed that it translocates out of the nucleus in microglia in the chronic CNS disease ALS, or amyotrophic lateral sclerosis.

Importantly, monomer HuR cannot pass through the nuclear envelope that acts as a regulatory membrane barrier between the nucleus and the cytoplasm. Only HuR dimers — made up by the coupling of two single HuR molecules — are able to translocate from nucleus to cytoplasm. This knowledge permitted collaborative research by Southern Research, of Birmingham, Alabama, and UAB, using high-throughput screening, to identify the small molecule drug SRI-42127 that inhibits dimerization of HuR.

In the current study, King, Nabors, Natalia Filippova, Ph.D., and UAB colleagues tested the biological relevance of SRI-42127, using lipopolysaccharide, or LPS, to activate glial cells to initiate the inflammatory cascade. The UAB researchers found that treatment with SRI-42127 suppressed HuR translocation from the nucleus to the cytoplasm in LPS-activated glial cells, both in tissue culture and in mice. SRI-42127 also significantly attenuated the production of proinflammatory mediators, including the cytokines IL1β, IL-6, TNF-α and iNOS, and the chemokines CXCL1 and CCL2.

Furthermore, SRI-42127 suppressed microglial activation in mouse brains, and it attenuated the recruitment of immune-cell neutrophils and monocytes into the CNS from outside the blood-brain barrier. Such an entry of neutrophils and monocytes can exacerbate inflammation in the brain or spinal cord. In summary, SRI-42127 penetrated the blood-brain barrier and quickly suppressed neuroinflammatory responses.

“Our findings,” King and Nabors said, “underscore HuR’s critical role in promoting glial activation and the potential for SRI-42127 and other HuR inhibitors to treat neurological diseases driven by this activation.”

In unpublished work in collaboration with Robert Sorge, Ph.D., associate professor in the Department of Psychology, UAB College of Arts and Sciences, King and Nabors have found potential beneficial effects of SRI-42127 to reduce neuropathic pain, a condition that is triggered by microglial-induced neuroinflammation. “This would be a non-opioid approach to treating pain,” they said.

Any future potential clinical treatments will require finesse.

“Therapeutic targeting of glia in CNS disease is a balancing act since these cells also exert neuroprotective and neuroplastic effects, depending on the phase of recovery from CNS injury or stage of neurodegenerative disease,” King and Nabors said. “In the initial phases after spinal cord injury, traumatic brain injury or stroke, the pro-inflammatory activation of glia worsens secondary tissue injury and triggers pathways of chronic neuropathic pain, in contrast to the more chronic phases where glia become protective. In neurodegenerative processes like ALS and Alzheimer’s, glia also play changing roles during the course of the disease.”

Co-authors with King, Nabors and Filippova in the current study, “SRI-42127, a novel small molecule inhibitor of the RNA regulator HuR, potently attenuates glial activation in a model of lipopolysaccharide-induced neuroinflammation,” are Rajeshwari Chellappan, Abhishek Guha, Ying Si, Thaddaeus Kwan, Xiuhua Yang, Anish S. Myneni, Shriya Meesala and Ashley S. Harms, UAB Department of Neurology.

Support came from National Institutes of Health grants NS092651 and NS111275-01, and United States Department of Veterans Affairs grant BX001148.

In their long collaboration, King and Nabors have used glioblastoma, a primary brain cancer, as a disease model to study HuR because many of the factors that drive neuroinflammation also promote glioblastoma growth. Nabors has focused on the tumor-suppressive properties of SRI-42127 and its potential use in the treatment of glioblastoma and other cancers.

Our closest animal relatives face a precarious future: Half of the world’s roughly 500 primate species are at risk of extinction due to human activities such as hunting, trapping and deforestation. But the demise of the world’s threatened primates could trigger even more species extinctions for the parasites that lurk on and in them, according to a Duke University-led study.

“If all the primates that are threatened with extinction really do die out, they won’t be the only species that go extinct,” said first author James Herrera of the Duke Lemur Center. “It could also be twice that many parasites.”

“That’s a whole realm of biodiversity that could be going extinct without us even noticing,” Herrera said. “There’s so little that we know about what they do in the body, that we don’t even know what we’re losing.”

One previous study suggests that some 85% to 95% of the parasitic worms of animals aren’t even known to science yet, much less evaluated by the authoritative extinction ‘Red List’ kept by the International Union for Conservation of Nature (IUCN).

Herrera admits this may seem like an odd thing to get worked up about, given all our efforts to deworm and delouse ourselves and our pets. To most people, parasites are “something we want to eradicate, rather than conserve,” Herrera said.

The thought of alien creatures biting, wriggling, squirming, and nestling into the warm wet folds of the intestines makes most people shudder. But parasites don’t always cause noticeable symptoms or make their hosts sick, Herrera said. Parasites can even have some surprising benefits, such as when worms in the gut help the body ward off other infections, or keep autoimmune disorders in check.

To gauge the potential loss of biodiversity if primates go extinct, Herrera and Duke professors Charlie Nunn and James Moody used network analysis techniques to measure the potential ripple effects on the parasites that set up camp in or on primate bodies. Their work appeared Sept. 20 in the journal Philosophical Transactions B.

In their model, species are connected in complex webs of interactions involving 213 primates — monkeys, apes, lemurs and galagos — and 763 worms, mites, protists, and other parasites known to infect them. When one primate host disappears, the parasites connected to it can no longer depend on it for survival. Sever enough of these connections, and their loss sets off a deadly cascade where one extinction begets another.

It’s a bit like the classic kids’ game, KerPlunk, Herrera said. You have a clear tube filled with marbles, which are resting on top of a web of crisscrossing sticks. Removing one or two sticks — or in this case, primate hosts — from the network does little harm, because the marbles are still supported by the remaining sticks. But as the game goes on and fewer sticks remain, it gets harder to keep the marbles from crashing down.

Currently, 108 of the 213 primate species in their dataset are considered threatened by the IUCN. The team found that if all those species were to go kaput, an additional 250 parasites could be doomed as well, and that 176 of these parasite species have no other suitable hosts.

The extinction cascade will likely be worse in isolated places like the island of Madagascar, the study revealed. There, shrinking forests, illegal hunting and collection for the pet trade are pushing 95% of lemur species ever closer to the brink, and more than 60% of lemur parasites inhabit a single host.

For instance, at least two species of nematode worms depend on the aye-aye, a long-fingered, bushy-tailed lemur with beaver-like teeth. If the aye-aye dies out, so too will the worms it carries.

The researchers say they aren’t able to predict, from their analyses, how many of the parasites in their dataset could potentially avert extinction by jumping ship and adapting to new hosts that are more abundant. But some of the most notorious diseases in humans, such as malaria, AIDS caused by HIV and yellow fever, got their start in other primates before spilling over to people, for instance when we share a watering hole, or when we butcher them for meat.

“It’s not that hard to imagine,” Herrera said.

The study is part of a special issue of Philosophical Transactions B devoted to infectious disease macroecology.

This research was supported by grants from the National Institutes of Health (NIH R25HD079352), the National Science Foundation (DEB-0211908, EF-0723939/0904359, BCS-1355902) and Duke University.